Pathophysiology of the ascending aorta: Impact of dilation and valve phenotype on large-scale blood flow coherence detected by 4D flow MRI.

BACKGROUND AND OBJECTIVE: The evidence on the role of hemodynamics in aorta pathophysiology has yet to be robustly translated into clinical applications, to improve risk stratification of aortic diseases. Motivated by the need to enrich the current understanding of the pathophysiology of the ascending aorta (AAo), this study evaluates in vivo how large-scale aortic flow coherence is affected by AAo dilation and aortic valve phenotype. METHODS: A complex networks-based approach is applied to 4D flow MRI data to quantify subject-specific AAo flow coherence in terms of correlation between axial velocity waveforms and the aortic flow rate waveform along the cardiac cycle. The anatomical length of persistence of such correlation is quantified using the recently proposed network metric average weighted curvilinear distance (AWCD). The analysis considers 107 subjects selected to allow an ample stratification in terms of aortic valve morphology, absence/presence of AAo dilation and of aortic valve stenosis. RESULTS: The analysis highlights that the presence of AAo dilation as well as of bicuspid aortic valve phenotype breaks the physiological AAo flow coherence, quantified in terms of AWCD. Of notice, it emerges that cycle-average blood flow rate and relative AAo dilation are main determinants of AWCD, playing opposite roles in promoting and hampering the persistence of large-scale flow coherence in AAo, respectively. CONCLUSIONS: The findings of this study can contribute to broaden the current mechanistic link between large-scale blood flow coherence and aortic pathophysiology, with the prospect of enriching the existing tools for the in vivo non-invasive hemodynamic risk assessment for aortic diseases onset and progression.

Hemodynamics and wall shear metrics in a pulmonary autograft: Comparing a fluid-structure interaction and computational fluid dynamics approach.

OBJECTIVE: In young patients, aortic valve disease is often treated by placement of a pulmonary autograft (PA) which adapts to its new environment through growth and remodeling. To better understand the hemodynamic forces acting on the highly distensible PA in the acute phase after surgery, we developed a fluid-structure interaction (FSI) framework and comprehensively compared hemodynamics and wall shear-stress (WSS) metrics with a computational fluid dynamic (CFD) simulation. METHODS: The FSI framework couples a prestressed non-linear hyperelastic arterial tissue model with a fluid model using the in-house coupling code CoCoNuT. Geometry, material parameters and boundary conditions are based on in-vivo measurements. Hemodynamics, time-averaged WSS (TAWSS), oscillatory shear index (OSI) and topological shear variation index (TSVI) are evaluated qualitatively and quantitatively for 3 different sheeps. RESULTS: Despite systolic-to-diastolic volumetric changes of the PA in the order of 20 %, the point-by-point correlation of TAWSS and OSI obtained through CFD and FSI remains high (r > 0.9, p < 0.01) for TAWSS and (r > 0.8, p < 0.01) for OSI). Instantaneous WSS divergence patterns qualitatively preserve similarities, but large deformations of the PA leads to a decrease of the correlation between FSI and CFD resolved TSVI (r < 0.7, p < 0.01). Moderate co-localization between FSI and CFD is observed for low thresholds of TAWSS and high thresholds of OSI and TSVI. CONCLUSION: FSI might be warranted if we were to use the TSVI as a mechano-biological driver for growth and remodeling of PA due to varying intra-vascular flow structures and near wall hemodynamics because of the large expansion of the PA.

Blood Flow Energy Identifies Coronary Lesions Culprit of Future Myocardial Infarction.

The present study establishes a link between blood flow energy transformations in coronary atherosclerotic lesions and clinical outcomes. The predictive capacity for future myocardial infarction (MI) was compared with that of established quantitative coronary angiography (QCA)-derived predictors. Angiography-based computational fluid dynamics (CFD) simulations were performed on 80 human coronary lesions culprit of MI within 5 years and 108 non-culprit lesions for future MI. Blood flow energy transformations were assessed in the converging flow segment of the lesion as ratios of kinetic and rotational energy values (KER and RER, respectively) at the QCA-identified minimum lumen area and proximal lesion sections. The anatomical and functional lesion severity were evaluated with QCA to derive percentage area stenosis (%AS), vessel fractional flow reserve (vFFR), and translesional vFFR (ΔvFFR). Wall shear stress profiles were investigated in terms of topological shear variation index (TSVI). KER and RER predicted MI at 5 years (AUC = 0.73, 95% CI 0.65-0.80, and AUC = 0.76, 95% CI 0.70-0.83, respectively; p < 0.0001 for both). The predictive capacity for future MI of KER and RER was significantly stronger than vFFR (p = 0.0391 and p = 0.0045, respectively). RER predictive capacity was significantly stronger than %AS and ΔvFFR (p = 0.0041 and p = 0.0059, respectively). The predictive capacity for future MI of KER and RER did not differ significantly from TSVI. Blood flow kinetic and rotational energy transformations were significant predictors for MI at 5 years (p < 0.0001). The findings of this study support the hypothesis of a biomechanical contribution to the process of plaque destabilization/rupture leading to MI.

Influence of intracoronary hemodynamic forces on atherosclerotic plaque phenotypes.

BACKGROUND AND AIMS: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition. METHODS: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained. RESULTS: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m-1, p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002). CONCLUSIONS: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features. CLINICAL TRIAL REGISTRATION: https://clinicaltrials,gov/ct2/show/NCT03782688.

Impact of wall displacements on the large-scale flow coherence in ascending aorta.

In the context of aortic hemodynamics, uncertainties affecting blood flow simulations hamper their translational potential as supportive technology in clinics. Computational fluid dynamics (CFD) simulations under rigid-walls assumption are largely adopted, even though the aorta contributes markedly to the systemic compliance and is characterized by a complex motion. To account for personalized wall displacements in aortic hemodynamics simulations, the moving-boundary method (MBM) has been recently proposed as a computationally convenient strategy, although its implementation requires dynamic imaging acquisitions not always available in clinics. In this study we aim to clarify the real need for introducing aortic wall displacements in CFD simulations to accurately capture the large-scale flow structures in the healthy human ascending aorta (AAo). To do that, the impact of wall displacements is analyzed using subject-specific models where two CFD simulations are performed imposing (1) rigid walls, and (2) personalized wall displacements adopting a MBM, integrating dynamic CT imaging and a mesh morphing technique based on radial basis functions. The impact of wall displacements on AAo hemodynamics is analyzed in terms of large-scale flow patterns of physiological significance, namely axial blood flow coherence (quantified applying the Complex Networks theory), secondary flows, helical flow and wall shear stress (WSS). From the comparison with rigid-wall simulations, it emerges that wall displacements have a minor impact on the AAo large-scale axial flow, but they can affect secondary flows and WSS directional changes. Overall, helical flow topology is moderately affected by aortic wall displacements, whereas helicity intensity remains almost unchanged. We conclude that CFD simulations with rigid-wall assumption can be a valid approach to study large-scale aortic flows of physiological significance.

Smartphone-based particle image velocimetry for cardiovascular flows applications: A focus on coronary arteries.

An experimental set-up is presented for the in vitro characterization of the fluid dynamics in personalized phantoms of healthy and stenosed coronary arteries. The proposed set-up was fine-tuned with the aim of obtaining a compact, flexible, low-cost test-bench for biomedical applications. Technically, velocity vector fields were measured adopting a so-called smart-PIV approach, consisting of a smartphone camera and a low-power continuous laser (30 mW). Experiments were conducted in realistic healthy and stenosed 3D-printed phantoms of left anterior descending coronary artery reconstructed from angiographic images. Time resolved image acquisition was made possible by the combination of the image acquisition frame rate of last generation commercial smartphones and the flow regimes characterizing coronary hemodynamics (velocities in the order of 10 cm/s). Different flow regimes (Reynolds numbers ranging from 20 to 200) were analyzed. The smart-PIV approach was able to provide both qualitative flow visualizations and quantitative results. A comparison between smart-PIV and conventional PIV (i.e., the gold-standard experimental technique for bioflows characterization) measurements showed a good agreement in the measured velocity vector fields for both the healthy and the stenosed coronary phantoms. Displacement errors and uncertainties, estimated by applying the particle disparity method, confirmed the soundness of the proposed smart-PIV approach, as their values fell within the same range for both smart and conventional PIV measured data (≈5% for the normalized estimated displacement error and below 1.2 pixels for displacement uncertainty). In conclusion, smart-PIV represents an easy-to-implement, low-cost methodology for obtaining an adequately robust experimental characterization of cardiovascular flows. The proposed approach, to be intended as a proof of concept, candidates to become an easy-to-handle test bench suitable for use also outside of research labs, e.g., for educational or industrial purposes, or as first-line investigation to direct and guide subsequent conventional PIV measurements.

Divergence of the normalized wall shear stress as an effective computational template of low-density lipoprotein polarization at the arterial blood-vessel wall interface.

BACKGROUND AND OBJECTIVE: Near-wall transport of low-density lipoproteins (LDL) in arteries plays a relevant role in the initiation of atherosclerosis. Although it can be modelled in silico by coupling the Navier-Stokes equations with the 3D advection-diffusion (AD) equation, the associated computational cost is high. As wall shear stress (WSS) represents a first-order approximation of the near-wall velocity in arteries, we aimed at identifying computationally convenient WSS-based quantities to infer LDL near-wall transport based on the underlying near-wall hemodynamics in five models of three human arterial districts (aorta, carotid bifurcations, coronary arteries). The simulated LDL transport and its WSS-based surrogates were qualitatively compared with in vivo longitudinal measurements of wall thickness growth on the coronary artery models. METHODS: Numerical simulations of blood flow coupled with AD equations for LDL transport and blood-wall transfer were performed. The co-localization of the simulated LDL concentration polarization patterns with luminal surface areas characterized by low cycle-average WSS, near-wall flow stagnation and WSS attracting patterns was quantitatively assessed by the similarity index (SI). In detail, the latter two represent features of the WSS topological skeleton, obtained respectively through the Lagrangian tracking of surface-born particles, and the Eulerian analysis of the divergence of the normalized cycle-average WSS vector field. RESULTS: Convergence of the solution of the AD problem required the simulation of 3 (coronary artery) to 10 (aorta) additional cardiac cycles with respect to the Navier-Stokes problem. Co-localization results underlined that WSS topological skeleton features indicating near-wall flow stagnation and WSS attracting patterns identified LDL concentration polarization profiles more effectively than low WSS, as indicated by higher SI values (SI range: 0.17-0.50 for low WSS; 0.24-0.57 for WSS topological skeleton features). Moreover, the correspondence between the simulated LDL uptake and WSS-based quantities profiles with the in vivo measured wall thickness growth in coronary arteries appears promising. CONCLUSIONS: The recently introduced Eulerian approach for identifying WSS attracting patterns from the divergence of normalized WSS provides a computationally affordable template of the LDL polarization at the arterial blood-wall interface without simulating the AD problem. It thus candidates as an effective biomechanical tool for elucidating the mechanistic link amongst LDL transfer at the arterial blood-wall interface, WSS and atherogenesis.

Coronary Artery Stenting Affects Wall Shear Stress Topological Skeleton.

Despite the important advancements in the stent technology for the treatment of diseased coronary arteries, major complications still affect the postoperative long-term outcome. The stent-induced flow disturbances, and especially the altered wall shear stress (WSS) profile at the strut level, play an important role in the pathophysiological mechanisms leading to stent thrombosis (ST) and in-stent restenosis (ISR). In this context, the analysis of the WSS topological skeleton is gaining more and more interest by extending the current understanding of the association between local hemodynamics and vascular diseases. This study aims to analyze the impact that a deployed coronary stent has on the WSS topological skeleton. Computational fluid dynamics (CFD) simulations were performed in three stented human coronary artery geometries reconstructed from clinical images. The selected cases presented stents with different designs (i.e., two contemporary drug-eluting stents and one bioresorbable scaffold) and included regions with stent malapposition or overlapping. A recently proposed Eulerian-based approach was applied to analyze the WSS topological skeleton features. The results highlighted that the presence of single or multiple stents within a coronary artery markedly impacts the WSS topological skeleton. In particular, repetitive patterns of WSS divergence were observed at the luminal surface, highlighting a WSS contraction action exerted proximal to the stent struts and a WSS expansion action distal to the stent struts. This WSS action pattern was independent from the stent design. In conclusion, these findings could contribute to a deeper understanding of the hemodynamics-driven processes underlying ST and ISR.

Risk of myocardial infarction based on endothelial shear stress analysis using coronary angiography.

BACKGROUND AND AIMS: Wall shear stress (WSS) has been associated with atherogenesis and plaque progression. The present study assessed the value of WSS analysis derived from conventional coronary angiography to detect lesions culprit for future myocardial infarction (MI). METHODS AND RESULTS: Three-dimensional quantitative coronary angiography (3DQCA), was used to calculate WSS and pressure drop in 80 patients. WSS descriptors were compared between 80 lesions culprit of future MI and 108 non-culprit lesions (controls). Endothelium-blood flow interaction was assessed by computational fluid dynamics (10.8 ± 1.41 min per vessel). Median time between baseline angiography and MI was 25.9 (21.9-29.8) months. Mean patient age was 70.3 ± 12.7. Clinical presentation was STEMI in 35% and NSTEMI in 65%. Culprit lesions showed higher percent area stenosis (%AS), translesional vFFR difference (ΔvFFR), time-averaged WSS (TAWSS) and topological shear variation index (TSVI) compared to non-culprit lesions (p < 0.05 for all). TSVI was superior to TAWSS in predicting MI (AUC-TSVI = 0.77, 95%CI 0.71-0.84 vs. AUC-TAWSS = 0.61, 95%CI 0.53-0.69, p < 0.001). The addition of TSVI increased predictive and reclassification abilities compared to a model based on %AS and ΔvFFR (NRI = 1.04, p < 0.001, IDI = 0.22, p < 0.001). CONCLUSIONS: A 3DQCA-based WSS analysis was feasible and can identify lesions culprit for future MI. The combination of area stenoses, pressure gradients and WSS predicted the occurrence of MI. TSVI, a novel WSS descriptor, showed strong predictive capacity to detect lesions prone to cause MI.

Early Atherosclerotic Changes in Coronary Arteries are Associated with Endothelium Shear Stress Contraction/Expansion Variability.

Although unphysiological wall shear stress (WSS) has become the consensus hemodynamic mechanism for coronary atherosclerosis, the complex biomechanical stimulus affecting atherosclerosis evolution is still undetermined. This has motivated the interest on the contraction/expansion action exerted by WSS on the endothelium, obtained through the WSS topological skeleton analysis. This study tests the ability of this WSS feature, alone or combined with WSS magnitude, to predict coronary wall thickness (WT) longitudinal changes. Nine coronary arteries of hypercholesterolemic minipigs underwent imaging with local WT measurement at three time points: baseline (T1), after 5.6 ± 0.9 (T2), and 7.6 ± 2.5 (T3) months. Individualized computational hemodynamic simulations were performed at T1 and T2. The variability of the WSS contraction/expansion action along the cardiac cycle was quantified using the WSS topological shear variation index (TSVI). Alone or combined, high TSVI and low WSS significantly co-localized with high WT at the same time points and were significant predictors of thickening at later time points. TSVI and WSS magnitude values in a physiological range appeared to play an atheroprotective role. Both the variability of the WSS contraction/expansion action and WSS magnitude, accounting for different hemodynamic effects on the endothelium, (1) are linked to WT changes and (2) concur to identify WSS features leading to coronary atherosclerosis.

Wall Shear Stress Topological Skeleton Independently Predicts Long-Term Restenosis After Carotid Bifurcation Endarterectomy.

Wall Shear Stress (WSS) topological skeleton, composed by fixed points and the manifolds linking them, reflects the presence of blood flow features associated to adverse vascular response. However, the influence of WSS topological skeleton on vascular pathophysiology is still underexplored. This study aimed to identify direct associations between the WSS topological skeleton and markers of vascular disease from real-world clinical longitudinal data of long-term restenosis after carotid endarterectomy (CEA). Personalized computational hemodynamic simulations were performed on a cohort of 13 carotid models pre-CEA and at 1 month after CEA. At 60 months after CEA, intima-media thickness (IMT) was measured to detect long-term restenosis. The analysis of the WSS topological skeleton was carried out by applying a Eulerian method based on the WSS vector field divergence. To provide objective thresholds for WSS topological skeleton quantitative analysis, a computational hemodynamic dataset of 46 ostensibly healthy carotid bifurcation models was considered. CEA interventions did not completely restore physiological WSS topological skeleton features. Significant associations emerged between IMT at 60 months follow-up and the exposure to (1) high temporal variation of WSS contraction/expansion (R2 = 0.51, p < 0.05), and (2) high fixed point residence times, weighted by WSS contraction/expansion strength (R2 = 0.53, p < 0.05). These WSS topological skeleton features were statistically independent from the exposure to low WSS, a previously reported predictor of long-term restenosis, therefore representing different hemodynamic stimuli and potentially impacting differently the vascular response. This study confirms the direct association between WSS topological skeleton and markers of vascular disease, contributing to elucidate the mechanistic link between flow disturbances and clinical observations of vascular lesions.

Deciphering ascending thoracic aortic aneurysm hemodynamics in relation to biomechanical properties.

The degeneration of the arterial wall at the basis of the ascending thoracic aortic aneurysm (ATAA) is a complex multifactorial process, which may lead to clinical complications and, ultimately, death. Individual genetic, biological or hemodynamic factors are inadequate to explain the heterogeneity of ATAA development/progression mechanisms, thus stimulating the analysis of their complex interplay. Here the disruption of the hemodynamic environment in the ATAA is investigated integrating patient-specific computational hemodynamics, CT-based in vivo estimation of local aortic stiffness and advanced fluid mechanics methods of analysis. The final aims are (1) deciphering the ATAA spatiotemporal hemodynamic complexity and its link to near-wall topological features, and (2) identifying the existing links between arterial wall degeneration and hemodynamic insult. Technically, two methodologies are applied to computational hemodynamics data, the wall shear stress (WSS) topological skeleton analysis, and the Complex Networks theory. The same analysis was extended to the healthy aorta. As main findings of the study, we report that: (1) different spatiotemporal heterogeneity characterizes the ATAA and healthy hemodynamics, that markedly reflect on their WSS topological skeleton features; (2) a link (stronger than canonical WSS-based descriptors) emerges between the variation of contraction/expansion action exerted by WSS on the endothelium along the cardiac cycle, and ATAA wall stiffness. The findings of the study suggest the use of advanced methods for a deeper understanding of the hemodynamics disruption in ATAA, and candidate WSS topological skeleton features as promising indicators of local wall degeneration.

Hemodialysis arterio-venous graft design reducing the hemodynamic risk of vascular access dysfunction.

Although arterio-venous grafts (AVGs) represent the second choice as permanent vascular access for hemodialysis, this solution is still affected by a relevant failure rate due to graft thrombosis, and development of neointimal hyperplasia (IH) at the distal vein. As a key role in these processes has been attributed to the abnormal hemodynamics establishing in the distal vein, the optimization of AVGs design aimed at minimizing flow disturbances would reduce AVG hemodynamic-related risks. In this study we used computational fluid dynamics to investigate the impact of alternative AVG designs on the reduction of IH and thrombosis risk at the distal venous anastomosis. The performance of the newly designed AVGs was compared to that of commercially available devices. In detail, a total of eight AVG models in closed-loop configuration were constructed: two models resemble the commercially available straight conventional and helical-shaped AVGs; six models are characterized by the insertion of a flow divider (FD), straight or helical shaped, differently positioned inside the graft. Unfavorable hemodynamic conditions were analyzed by assessing the exposure to disturbed shear at the distal vein. Bulk flow was investigated in terms of helical blood flow features, potential thrombosis risk, and pressure drop over the graft. Findings from this study clearly show that using a helically-shaped FD located at the venous side of the graft could induce beneficial helical flow patterns that, minimizing flow disturbances, reduce the IH-related risk of failure at the distal vein, with a clinically irrelevant increase in thrombosis risk and pressure drop over the graft.

Spatiotemporal Hemodynamic Complexity in Carotid Arteries: An Integrated Computational Hemodynamics and Complex Networks-Based Approach.

OBJECTIVE: The study of the arterial hemodynamics is essential for a better understanding of the risks associated with the onset/progression of vascular disease. However, conventional quantification and visualization paradigms are not sufficient to fully capture the spatiotemporal evolution of correlated blood flow patterns and their "sphere of influence" in complex vascular geometries. In the attempt to bridge this knowledge gap, an integrated computational hemodynamics and complex networks-based approach is proposed to unveil organization principles of cardiovascular flows. METHODS: The approach is applied to ten patient-specific hemodynamic models of carotid bifurcation, a vascular bed characterized by a complex hemodynamics and clinically-relevant disease. Correlation-based networks are built starting from time-histories of two fluid mechanics quantities of physiological significance, respectively (1) the blood velocity vector axial component locally aligned with the main flow direction, and (2) the kinetic helicity density. RESULTS: Unlike conventional hemodynamic analyses, here the spatiotemporal similarity of dynamic intravascular flow structures is encoded in a distance function. In the case of the carotid bifurcation, this study measures for the first time to what extent flow similarity is disrupted by vascular geometric features. CONCLUSION: It emerges that a larger bifurcation expansion, a hallmark of vascular disease, significantly disrupts the network topological connections between axial flow structures, reducing also their anatomical persistence length. On the contrary, connections in helical flow patterns are overall less geometry-sensitive. SIGNIFICANCE: The integrated approach proposed here, by exploiting the connections of hemodynamic patterns undergoing similar dynamical evolution, opens avenues for further comprehension of vascular physiopathology.

A Eulerian method to analyze wall shear stress fixed points and manifolds in cardiovascular flows.

Based upon dynamical systems theory, a fixed point of a vector field such as the wall shear stress (WSS) at the luminal surface of a vessel is a point where the vector field vanishes. Unstable/stable manifolds identify contraction/expansion regions linking fixed points. The significance of such WSS topological features lies in their strong link with "disturbed" flow features like flow stagnation, separation and reversal, deemed responsible for vascular dysfunction initiation and progression. Here, we present a Eulerian method to analyze WSS topological skeleton through the identification and classification of WSS fixed points and manifolds in complex vascular geometries. The method rests on the volume contraction theory and analyzes the WSS topological skeleton through the WSS vector field divergence and Poincar[Formula: see text] index. The method is here applied to computational hemodynamics models of carotid bifurcation and intracranial aneurysm. An in-depth analysis of the time dependence of the WSS topological skeleton along the cardiac cycle is provided, enriching the information obtained from cycle-average WSS. Among the main findings, it emerges that on the carotid bifurcation, instantaneous WSS fixed points co-localize with cycle-average WSS fixed points for a fraction of the cardiac cycle ranging from 0 to [Formula: see text]; a persistent instantaneous WSS fixed point confined on the aneurysm dome does not co-localize with the cycle-average low-WSS region. In conclusion, the here presented approach shows the potential to speed up studies on the physiological significance of WSS topological skeleton in cardiovascular flows, ultimately increasing the chance of finding mechanistic explanations to clinical observations.